DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant's election with traverse of group I (claims 2, 6, 10, 13, 17, 25, 28, 33, 35, 43, 46, 49, and 50 and APOC3, siRNAc17) and species (modification pattern: in the direction from the 5’ end to the 3’ end, the 3rd or 5th nucleotide in the nucleotide sequence II is the stabilizing nucleotide, as set forth in claim 2 and stabilizing modified nucleotide is 2’-O-methyoxyethyl) in the reply filed on 8/6/26 is acknowledged. Claims 1 and 32 were linking claims. The traversal is on the ground(s) that CN 110997919 and CN110945130 do not teach the special technical feature because CN ‘919 does not teach or suggest “the siRNA comprising a stabilizing modified nucleotide(s) has increased thermal stability and exhibits significantly reduced off-target effects”. Furthermore, CN ’919 teaches a non-fluoro modified nucleotides can be any modification type, any combination at any position, except for positions 2, 6, 14, and 6 of the nucleotide sequence 2, and any numbers. This is found persuasive because CN’919 taken with CN’130 do not specifically teach or suggest at least one stabilizing modifying nucleotide at 3rd to 6th position in the nucleotide sequence 2, counting from the 5’ end of the sequence; and none of the other nucleotides in the sequence are stabilizing modifying nucleotide other than at least one nucleotide at 3rd to 9th nucleotides in the nucleotide sequence 2. However, in view of a reference cited in the prior art rejections under 102 and 103 (See Figure 6 of Prakash J. Med. Chem Vol. 48, pages 4727-4253, 2005, cited on an IDS, incorporated herein), the special technical does not make a contribution over the prior art.
The requirement is still deemed proper and is therefore made FINAL.
Claims 21, 39, 55-56 and 59-60 and the non-elected genes in claims 28 and 46 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 8/5/26.
Upon further consideration, ANGPTL3 is rejoined with the elected invention.
NOTE: applicant states the claims 1, 2, 6, 10, 13, 17, 25, 28, 32, 33, 35, 43, 46, 49, and 50 encompass the elected species. However, several of the claims listed by applicant are considered withdrawn to non-elected species. See page 6 of restriction mailed on 6/2/26 and applicant’s species election. Also see below.
The non-elected chemical modification in claim 10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 8/5/26.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Specification
The use of the term TRIZOL and siCHECK, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 28 is objected to because of the following informalities: Claim 28 refers to a nucleotide sequence of double stranded oligonucleotides (e.g., siRNAc17) and the nucleotide sequences in siRNAc17 have sequence identifiers. These sequences need to be listed in claim 2 to comply with sequence rules 37 CFR 1.821-1.825. See 37 CFR 1.821(d): (d) Where the description or claims of a patent application discuss a sequence that is set forth in the "Sequence Listing," in accordance with paragraph (c) of this section, reference must be made to the sequence by use of the sequence identifier (§ 1.823(a)(5) ), preceded by "SEQ ID NO:" or the like, in the text of the description or claims, even if the sequence is also embedded in the text of the description or claims of the patent application. Where a sequence is presented in a drawing, reference must be made to the sequence by use of the sequence identifier (§ 1.823(a)(5) ), either in the drawing or in the Brief Description of the Drawings, where the correlation between multiple sequences in the drawing and their sequence identifiers (§ 1.823(a)(5) ) in the Brief Description is clear. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 6, 10, 13, 17, 25, and 28 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claimed invention embraces a double stranded oligonucleotide (also known as siRNA) comprising a sense strand and an antisense strand, wherein the antisense strand has at least one stabilizing modified nucleotide in at least one of the 3rd-6th nucleotides from the 5’ end of the antisense strand, wherein the stabilizing modifying nucleotide refers to a nucleotide whose ribose hydroxyl group at the 2’ position is substituted with a stabilizing modification group and the group results in increased thermostability and steric hindrance greater than that of 2’-O-methyl.
Instant claim 6 embrace specific melting temperatures Tm of the double stranded oligonucleotide (an increase of at least 0.05 °C; 0.1-6 °C: or 0.5-4 °C in the melting temperature).
Instant claim 10 recites a large list of stabilizing modifications group.
The state of the art and currently disclose:
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See BENCHCHEM 2'-O-Methyl vs. 2'-O-Methoxyethyl Modified Oligonucleotides: A Comparative Guide 2026 pages 1-9. In view of this chart, it appears that the Tm for 2’-OMe and 2’-MOE overlap. An et al. (Molecular Therapy Nucleic Acids Vol. 36, pages 1-17, 2025) teach a nucleotide modification (2-formamido) that could be embraced by the claims based on the breadth of the genus of stabilizing modified nucleotides that would have a decreased thermodynamic stability.
A person of skill in the art would possess the knowledge that steric hindrance from bulky modification (2’-OME or 2’- MOE) generally increases thermal stability (melting temperature Tm of an siRNA). For example, see Hu et al. Signal Transduction and Targeted Therapy Vol. 5, pages 1-25, 2020, cited on an IDS and Terrazas et al. (Nucleic Acid Research 37, 346-353, 2009). Hu (supra) teaches that several chemical modifications can reduce the Tm value.
Other than 2’-O-methyoxyethyl, neither the prior art of record, and currently, nor the specification of the instant disclosure describe any other group that has an increase in thermostability and the steric hindrance of the stabilizing group is greater than that of 2’-O-methyl. The skilled artisan would have to further experiment with each species (sub-species) of group to determine if possess the desired biological activity.
The written description requirement for the claimed genus of stabilizing modified nucleotides having the desired biological activity is not satisfied through sufficient description of a representative number of species in the specification of the instant disclosure. In view of the state of the art and lack of written description in the specification, the as-filed specification does not disclose a “representative number of species” which would adequately described and be considered representative of the entire genus. There is a substantial variation within the genus of stabilizing modified nucleotide and the applicant does not escribe a sufficient variety of species to reflect the variation within the genus. See also MPEP §2163.
In view of the foregoing, it is clear that the specification of the instant disclosure fails to convey to the skilled artisan that the applicant had possession of the claimed genus of stabilizing agents having the desired biological activity in the instant claims as of the effective filing date.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 25 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 25 recites the limitation "the non-fluoro modified nucleotides" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 2, 6, 10, 13, and 25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Prakash J. Med. Chem Vol. 48, pages 4727-4253, 2005, cited on an IDS.
Prakash teaches phosphorothioate dsRNA molecules, wherein the nucleotides 3-5 and 6-9 in the antisense strand are modified with 2’-MOE complexed with a cationic lipid . See antisense strand labelled 26 and 27 and sense strand is labelled 2 in Figure 6.
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With respect to the functional limitation (the stabilizing modified nucleotide refers to a nucleotide whose ribose hydroxyl group at the 2' position is substituted with a stabilizing modification group; compared with a double-stranded oligonucleotide whose nucleotides at the corresponding positions are unmodified nucleotides, the double-stranded oligonucleotide comprising the stabilizing modified nucleotide has increased thermostability, and the steric hindrance of the stabilizing modification group is greater than that of 2'-O-methyl.) in instant claim 1 and instant claim 6 directed to an increase in thermostability of the double stranded oligonucleotide directed to an increase in the melting temperature Tm of the double stranded oligonucleotide, Prakash teaches the structural limitations of the claimed dsRNA, thus any property of the dsRNA would be considered an inherent property of the dsRNA taught by Praskash. See MPEP 2112.01(II): if the composition is physically the same, it must have the same properties.
In addition, Prakash discloses that 2’-MOE is bulkier than 2’-O-ME or 2’-F substituents.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 17, 28, 32, 33, 35, 43, 46, and 49-50 are rejected under 35 U.S.C. 103 as being unpatentable over Prakash J. Med. Chem Vol. 48, pages 4727-4253, 2005, cited on an IDS as applied to claims 1, 2, 6, 10, 13, and 25 above, and further in view of Zhang (WO2019105414; see English translation US 2021003263, cited on an IDS). ‘263 is the U.S. national stage application for ‘414. ‘263 will be cited in the following 103 rejection because ‘414 is in Chinese.
Prakash does not specifically teach a 2’F at positions 7-9 in the sense strand and nucleotides at positions 2, 6, 14, and 16 are 2’ F from the 5’ end of each strand; and other nucleotides in the sense and antisense strand are non-fluoro-modified nucleotides.
However, Zhang teaches ANGPTL3 siRNA covalently linked to a conjugate via a linker. See for example, pages 7-16 and 123-126. The siRNA has the following modifications: in the direction from 5′ terminal to 3′ terminal, the nucleotides at positions 7, 8 and 9 or at positions 5, 7, 8 and 9 the sense strand are fluoro modified nucleotides, and the nucleotides at the other positions in the sense strand are methoxy modified nucleotides; the nucleotides at positions 2, 6, 14 and 16 or at positions 2, 6, 8, 9, 14 and 16 of the nucleotide sequence in the antisense strand are fluoro modified nucleotides, and the nucleotides at the other positions in the antisense strand are methoxy modified nucleotides. A pharmaceutical composition, wherein the pharmaceutical composition comprises the siRNA and a pharmaceutically acceptable carrier. A siRNA conjugate comprising the siRNA and a conjugating group conjugated to the siRNA. The internucleotide linkage between the siRNA can be a phosphorothioate group, and the phosphorothioate linkage is present at least one of the following positions: the position between the first and second nucleotides at 5′ terminal of the sense strand; the position between the second and third nucleotides at 5′ terminal of the sense strand; the position between the first and second nucleotides at 3′ terminal of the sense strand; the position between the second and third nucleotides at 3′ terminal of the sense strand; the position between the first and second nucleotides at 5′ terminal of the antisense strand; the position between the second and third nucleotides at 5′ terminal of the antisense strand; the position between the first and second nucleotides at 3′ terminal of the antisense strand; and the position between the second and third nucleotides at 3′ terminal of the antisense strand.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of Prakash taken with Zhang, to try and incorporate a 2’F at positions 7-9 in the sense strand and nucleotides at positions 2, 6, 14, and 16 in the antisense strand are 2’ F from the 5’ end of each strand; and other nucleotides in the sense and antisense strand are non-fluoro-modified nucleotides of the dsRNA taught by Prakash with a reasonable expectation of success. See MPEP 2143(I)E. Prakash teaches that 2’F, 2’-O-Me and 2’-O-MOE are the most commonly used chemical modification in a siRNA (page 4247). Furthermore, studying the placement of these modifications to study their effect on RNAi activity was considered routine in the prior art as taught by Prakash (see entire document). See also MPEP 2144.05(II) Routine Optimization. One of ordinary skill in the art would have been motivated to try making the claimed dsRNA to determine it’s potential for therapeutic usage for decreasing ANGPTL3 expression. Zhang teaches that one of ordinary skill in the art can make the internucleotide linkage in the siRNA can be a phosphorothioate group, and the phosphorothioate linkage is present at least one of the following positions: the position between the first and second nucleotides at 5′ terminal of the sense strand; the position between the second and third nucleotides at 5′ terminal of the sense strand; the position between the first and second nucleotides at 3′ terminal of the sense strand; the position between the second and third nucleotides at 3′ terminal of the sense strand; the position between the first and second nucleotides at 5′ terminal of the antisense strand; the position between the second and third nucleotides at 5′ terminal of the antisense strand; the position between the first and second nucleotides at 3′ terminal of the antisense strand; and the position between the second and third nucleotides at 3′ terminal of the antisense strand. One of ordinary skill in the art would have been motivated to make a pharmaceutical composition comprising the dsRNA to assist in delivery to cells or for storage for future usage. A person of ordinary skill in the art would have been motivated to make an oligonucleotide conjugate comprising the dsRNA covalently or non-covalently linked via linker to a targeting group and/or auxiliary group to assist in delivery of the dsRNA to cells.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 2, 6, 10, 13, 17, 25, 28, 32-33, 35, 43, 46, and 49-50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, 8, 11, 14, 16, 19, 21, 26, 27, 33, 36, 38, 40, 42, 44, 45, 48-50 and 52-53 of copending Application No. 18576563 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both set of claims are directed to a APOC3 dsRNA (also known as siRNA) comprising a sense strand and an antisense strand, each strand having at least 19 nucleotides; the antisense strand is complementary to a region of an APOC3 gene; and at least one of the 3rd-6th nucleotides in the antisense strand is a stabilizing modified nucleotides (2’-O-methoxyethyl), wherein the stabilizing modified nucleotide has an increased thermostability and steric hindrance greater than 2’-O-methyl. The structural limitations of the claimed product recited in instant claims 2, 6, 10, 13, 17, 25, 28, 33, 35, 43, 46, and 49-50 are disclosed or made obvious by claims 2, 4, 8, 11, 14, 16, 19, 21, 26, 27, 33, 36, 38, 40, 42, 44, 45, and 48-50 of ‘563.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
See attached PTO-326 for disposition of claims.
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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636
